NZ625337B2 - Anticoagulant reversal agents - Google Patents
Anticoagulant reversal agents Download PDFInfo
- Publication number
- NZ625337B2 NZ625337B2 NZ625337A NZ62533712A NZ625337B2 NZ 625337 B2 NZ625337 B2 NZ 625337B2 NZ 625337 A NZ625337 A NZ 625337A NZ 62533712 A NZ62533712 A NZ 62533712A NZ 625337 B2 NZ625337 B2 NZ 625337B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- dap
- subject
- pharmaceutically acceptable
- anticoagulant
- Prior art date
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- IUYIRQQAVVYNBK-UHFFFAOYSA-N propane-1,2-diol;tetradecanoic acid Chemical compound CC(O)CO.CCCCCCCCCCCCCC(O)=O IUYIRQQAVVYNBK-UHFFFAOYSA-N 0.000 description 1
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- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
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- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
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- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical compound NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Abstract
Provided are compounds of the general formula (I), wherein the variables are as defined in the specification. In embodiments the compounds are represented by the general formulae (II) and (IV). Particularly preferred are piperazine-diarginine derivative compounds such as 2-Amino-5-guanidino-pentanoic acid (3-{4-[3-(2-amino-5-guanidinopentanoylamino)-propyl]-piperazin-1-yl}-propyl)-amide and 2-Amino-5-guanidino-pentanoic acid {5-[(2-amino-5-guanidinopentanoylamino)-methyl]-piperazin-2-ylmethyl}-amide. The compounds are useful for reversing the anticoagulant effects of coagulation inhibitors. c acid (3-{4-[3-(2-amino-5-guanidinopentanoylamino)-propyl]-piperazin-1-yl}-propyl)-amide and 2-Amino-5-guanidino-pentanoic acid {5-[(2-amino-5-guanidinopentanoylamino)-methyl]-piperazin-2-ylmethyl}-amide. The compounds are useful for reversing the anticoagulant effects of coagulation inhibitors.
Description
TITLE
ANTICOAGULANT REVERSAL AGENTS
FIELD OF THE INVENTION
[0001] The present invention generally discloses compounds that completely or
partially reverse anticoagulant effects of coagulation inhibitors, such as
unfractionated heparin (“UFH”), low molecular weight heparin (“LMWH”),
fondaparinux, and other antithrombin binding anticoagulants, as well as direct Xa
and IIa inhibitors.
BACKGROUND OF THE INVENTION
[0002] The coagulation cascade is a normal physiological process which aims at
preventing significant blood loss or hemorrhage following vascular injury. There
are times, however, when a blood clot (thrombus) will form when it is not
needed. For instance, some high risk conditions such as acute medical illness,
prolonged immobilization, surgery, or cancer can increase the risk of developing
a blood clot which can potentially lead to significant consequences such as
atherosclerotic cardiovascular disease and/or abnormal cardiac rhythms.
[0003] The coagulation cascade consists of a series of steps in which a protease
cleaves and subsequently activates the next protease in the sequence. Each
protease can activate several molecules of the next protease in the series,
amplifying this biological cascade. The final result of these reactions is to
convert fibrinogen, a soluble protein, to insoluble threads of fibrin. Together
with platelets, the fibrin threads form a stable blood clot.
[0004] Antithrombin (AT), a serine protease inhibitor, is the major plasma
inhibitor of coagulation proteases. AT blocks the coagulation cascade by, e.g.,
inhibiting thrombin (factor IIa) and activated factor X (factor Xa). Heparin
(unfractionated heparin) and low molecular weight heparins (LMWHs;
fractionated heparin) inhibit the coagulation process through binding to AT via a
pentasaccharide sequence. This binding leads to a conformational change of AT,
which accelerates its inhibition of factors IIa, Xa, and other proteases involved in
blood clotting. Once dissociated, heparin and LMWH are free to bind to another
antithrombin molecule and subsequently inhibit more thrombin and factor Xa.
[0005] Unfractionated heparin is a mixture of glycosaminoglycans (GAGs)
discovered in the liver of dogs to have anti-coagulant properties in 1916 by
McLean and Howell at Johns Hopkins University. In addition to
anti-coagulation, unfractionated heparin has been found to have other properties
including anti-inflammation and angiogenesis. LMWHs are heparins consisting
of short chains of polysaccharide, generally having molecular weight of less than
8000 Da. LMWH and heparin are both used to prevent blood from clotting inside
the body, but are used in different situations in the clinic.
[0006] Heparin is available as a liquid solution administered parenterally.
LMWH, such as enoxaparin, is a low molecular weight fraction of heparin. It is
also available as a liquid injectable solution. The currently available brands of
LMWH approved by FDA in the United States are LOVENOX® (generic name,
enoxaparin) and FRAGMIN ® (generic name, dalteparin).
[0007] Low molecular weight or fractionated heparin has greater specificity for
blood factor Xa and factor IIa activity than unfractionated heparin. Additionally,
LMWH has a more reproducible effect on activated partial thromboplastin time
(aPTT), a measure of coagulation time. LWMH has a lower incidence of Heparin
Induced Thrombocytopenia (HIT). Because LMWH has more predictable
efficacy and a lower incidence of adverse effects such as HIT, patients can inject
LMWH themselves at home, although it is also often used in the hospital. For
these reasons, LMWHs have become the market-leading anticoagulant.
[0008] Protamine, a positively charged molecule, can be used to reverse
anti-coagulation resulting from administration of highly negatively charged
unfractionated heparin or low molecular weight heparin (LMWH). Protamine is
a natural product that has been associated with supply problems, which highlights
a need for additional, ideally synthetic, reversal agent options. The anti-
coagulant activity of LMWH can be partially, but not fully, reversed by
intravenous administration of protamine. The reason for the reduced
anticoagulation reversal activity of protamine in the case of LMWH is believed to
be due to a lesser binding affinity for the LMWH fraction in the blood than
unfractionated heparin. Protamine must be administered slowly, due to
hypotensive effects and concerns regarding anaphylaxis.
[0009] Recently, additional anticoagulant agents have begun to gain regulatory
approval. Examples of such anticoagulants include dabigatran or PRADAXA®,
argatroban or ARGATROBAN®, rivaroxaban or XARELTO®, apixaban or
ELIQUIS®, edoxaban or LIXIANA®, and fondaparinux or ARIXTRA®. These
anticoagulants inhibit either factor IIa or factor Xa from propagating coagulation.
[0010] Anticoagulants such as dabigatran, fondaparinux, rivaroxaban and
apixaban have no approved reversal agent. The current state of the art for
dabigatran or PRADAXA® reversal is to employ activated charcoal to attempt to
remove dabigatran from the blood and to use blood transfusions. Other than
Eerenberg et al. Circulation. 2011 Oct 4;124(14):1573-9. Epub 2011 Sep 6.,
which reports that in a small clinical trial, prothrombin complex concentrate was
able to reverse dabigatran, but not rivaroxaban, there is no data or clinically
available antidote for reversing any of these coagulation Factor IIa or Xa
inhibitors. Therefore, when patients are anti-coagulated with these agents,
adverse effects associated with overdosing, particularly significant or fatal bleeds,
are much more dangerous than the side effects associated with administration of
unfractionated heparin. The lack of reversal agent therefore limits the use of
these drugs.
[0011] For these reasons, there is a longstanding, strong, unmet clinical need for
new anti-coagulation reversal agents.
SUMMARY OF THE INVENTION
[0012] In one aspect, the invention provides a compound represented by formula
II:
(II)
O
O
L' C Y'
Y C L
N M'
M N
H
H
N N
,
or a pharmaceutically acceptable salt thereof, wherein:
L and L’ are the same or different and are substituted or
unsubstituted alkylene chains that is C to C ;
1 10
M and M’ are the same or different and are substituted or
unsubstituted alkylene chain that is C to C that attaches to Y and to Y’,
1 10
respectively; and
Y and Y’ are each ; wherein the substituents of the C1 to C10
alkylene chains are selected from the group consisting of alkyl, hydroxyl,
hydroxyl alkyl, amino, amino alkyl and alkyl alkoxy.
[0012a] In another aspect, the invention provides a pharmaceutical composition
comprising the compound of the invention and a pharmaceutically acceptable
carrier.
[0012b] In another aspect, the invention relates to a use of a compound of the
invention or a pharmaceutically acceptable salt thereof in the manufacture of a
medicament for completely or partially reversing an anticoagulant effect of a
coagulation inhibitor in a subject in need thereof.
[0012c] In another aspect, the invention provides a diagnostic kit comprising the
compound of the invention.
[0012d] Certain statements that appear below are broader than what appears in the
statements of the invention above. These statements are provided in the interests
of providing the reader with a better understanding of the invention and its
practice. The reader is directed to the accompanying claim set which defines the
scope of the invention.
[0012e] Inhibitors of heparin, heparin fragments, fondaparinux and other factor
Xa or factor IIa inhibitors have been developed. The general structure of the anti-
coagulant reversal agents of interest is: R-Z-R’, where R and R’ are positively
charged agents at physiologic pH and can be the same or different molecules and
Z is a hydrophobic cyclic or fused ring compound. More specifically, the
inhibitor is represented by a compound of formula I or a pharmaceutically
acceptable salt thereof:
(I)
wherein:
A is a substituted or unsubstituted aromatic or non-aromatic, carbocyclic or
heterocyclic ring or a linear moiety;
L and L’ are the same or different and are linkers;
X and X’ are the same or different and are absent or are a functional group
that attaches the linker L to M and the linker L’ to M’, respectively;
M and M’ are the same or different and are absent or is a linker that
attaches X to Y and X’ to Y’, respectively; and
Y and Y’ are the same or different and are a moiety containing one or more
cationic atoms or groups or one or more groups that become cationic under
physiological conditions.
[0013] The compounds can be symmetrical or asymmetrical; that is, one or more
of L, L’, X, X’, M, M’, Y, or Y’ can be the same or different. The compounds
can be chiral (i.e., contain one or more chiral centers) or achiral.
[0014] In some embodiments, A is a heterocyclic moiety. In other embodiments,
A is a heterocyclic moiety and L and L’ are a substituted or unsubstituted
alkylene chain. In still other embodiments, A is a heterocyclic moiety, L and L’
are a substituted or unsubstituted alkylene chain, and X and X’ are –NH-C(=O)-.
In still other embodiments, A is a heterocyclic moiety, L and L’ are a substituted
or unsubstituted alkylene chain, X and X’ are –NH-C(=O)-, and M and M’ are a
substituted alkylene chain. In still other embodiments, A is a heterocyclic
moiety, L and L’ are a substituted or unsubstituted alkylene chain, X is –NH-
C(=O)-, M and M’ are a substituted alkylene chain, and Y and Y’ are a guanidine
moiety. In particular embodiments, A is a 1,4 or 2,5 disubstituted piperazine
ring.
[0015] In another embodiment the inhibitor is a compound represented by the
formula II or a pharmaceutically acceptable salt thereof:
(II)
O
O
Y C L L' C Y'
M N N M'
H H
N N
wherein each of L, L′, M, M′, Y and Y′ are as described herein.
[0016] In another embodiment the inhibitor is a compound represented by the
formula III or a pharmaceutically acceptable salt thereof:
O O
(III)
Y C L L' C Y'
M NH N N N M'
H
wherein L, L′, M, M′, Y and Y′ are as described herein.
[0017] In yet another embodiment the inhibitor is a compound represented by the
formula (IV) or pharmaceutically acceptable salt thereof:
G G (IV)
H H
Y'
Y CH N N CH
N N
(CH ) C (CH ) (CH ) C (CH )
2 2 2 m 2 n
n m
O O
wherein Y and Y′ are as described herein and n is 3 to 5, m is 3 to 6 and G is
selected from –NH and OH. Most preferably, G is amino.
2
[0018] Yet another embodiment the inhibitor is a compound represented by any
of formula II, III or IV and Y and Y′ are independently selected from the group
consisting of
NH
N
H
NH
2 and -NH
2.
[0019] Most preferably G is –NH and Y and Y′ are
2
NH
N
H
NH
2.
[0020] In the preferred embodiment, the compound is di-arginine piperazine
(DAP), depicted in formula V, or a related compound, depicted in formula VI, or
pharmaceutically acceptable salts of either compound:
(V)
O
O
H H
N
N
HN NH
NN NH NH
2 2
N N
H H
H N
NH
2 2
2-Aminoguanidino-pentanoic acid (3-{4-[3-(2-aminoguanidino-
pentanoylamino)-propyl]-piperazinyl}-propyl)-amide; or
(VI)
O
HN
NH
O
NH HN
HN NH
2
NH
H N H N NH
2
2
HN
NH
2
2-Aminoguanidino-pentanoic acid {5-[(2-aminoguanidino-
pentanoylamino)-methyl]-piperazinylmethyl}-amide.
[0021] In a specific embodiment, the compound of formula V is a stereoisomer
as depicted in formula VII:
(VII)
O O
NH HN
HN NH N N H N NH
2 2
NH HN
H N NH
2 2 .
[0022] In another specific embodiment, the compound of formula VI is a
stereoisomer as depicted in formula VIII:
(VIII)
O
NH HN
O
HN NH
NH HN
2
NH
H N H N NH
2
2
HN
NH
2 .
[0023] The compounds of the invention can be administered in a pharmaceutical
composition as an aqueous solution as a bolus and/or intravenous infusion,
subcutaneous injection, or orally. In the preferred embodiment, the compounds
are administered by injection (intravenous, intramuscular or subcutaneous) in a
carrier such as distilled sterile water, saline, buffered saline, or another
pharmaceutically acceptable excipient for injection. In some embodiments, the
inhibitor may be administered orally, to a mucosal surface (nasal, pulmonary,
vaginal, rectal or buccal) or by depot.
[0024] The compounds of the invention may be administered in pharmaceutical
composition to the patient in need of reversal of heparin, LMWH or other
thrombin inhibitor-mediated anticoagulation in an effective amount to restore
normal coagulation and hemostasis. The pharmaceutical compositions including
the compound of the inventions are suitable for hospital use or in non-emergency
home reversal. It is administered to the patient in need of reversal of heparin,
LMWH or other thrombin inhibitor mediated anticoagulation in an effective
amount to restore coagulation. The compounds and pharmaceutical compositions
described herein can also be used to reduce the activity of heparin-binding
growth factors and/or for reversing completely or in part a combination of one or
more Factor IIa and/or Factor Xa anticoagulant agents.
[0025] Thus, the compounds of the invention can be used in a method of
completely or partially reversing an anticoagulant effect of a coagulation
inhibitor. The compounds of the invention can also be used as a part of a
diagnostic kit, e.g., a diagnostic kit for determining concentration of an
anticoagulant in the blood.
[0026] Examples demonstrate that DAP directly bound rivaroxaban, apixaban,
unfractionated heparin, fondaparinux, and LMWH, reversing anticoagulant
activity. DAP reversed oral rivaroxaban and subcutaneous LMWH
anticoagulation in vivo as measured by aPTT and subcutaneous fondaparinux as
measured by Xa activity in rats. DAP reversal, confirmed by statistically
significant reduction in blood loss in tail rat transection assay, was shown for
apixaban, dabigatran, edoxaban, and rivaroxaban. DAP completely reversed
apixaban and rivaroxaban at a dose mass ratio of about 10:1 DAP:anticoagulant
in human blood ex vivo as measured using an anti-Xa kit. DAP exhibited a dose-
dependent reversal of apixaban and rivaroxaban in human blood ex vivo.
Rivaroxaban reversal in freshly drawn human whole blood was confirmed by
aPTT measurements ex vivo. DAP did not bind argatroban concentrations up to
1:1000 in vitro. DAP reversed oral dabigatran in vivo in rats as measured by
aPTT. Argatroban dosed rats remained anticoagulated after a 200x IV dose of
DAP, showing that DAP is safe and that the reversal interaction is specific for the
heparins and new oral anticoagulants. In summary, the examples demonstrate
complexation of DAP to heparin and LMWH and that DAP serves as an excellent
reversal agent for heparin, heparin-like compounds and other thrombin inhibitors
including dabigatran, approved low molecular weight heparins, as well as
rivaroxaban (XARELTO®), fondaparinux (ARIXTRA®), edoxaban
(LIXIANA®), and apixaban (ELIQUIS®), as tested in in vitro assays with
human blood, anti-Xa and aPTT tests and/or in vivo in a rat tail transection assay.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Figure 1 is a graph of heat flow versus temperature as measured by
o
differential scanning calorimetry (DCS) in which DAP is heated from -20 C to
o o o
200 C (“1” or “first heat”), cooled to -20 C, and heated back to 200 C (“2” or
“second heat”).
[0028] Figure 2 is a graph of DAP alone, UFH alone, and DAP-UFH
combination, as a function of volume percent compared to size (d.nm) as
measured by Dynamic Light Scattering (DLS).
[0029] Figure 3 is a graph of DAP alone, rivaroxaban alone and DAP-
rivaroxaban in ratios of 1:1 and 10:1, DAP:rivaroxaban, as a function of volume
(percent) compared to size (d.nm) as measured by DLS.
[0030] Figure 4 is a graph of DAP alone, apixaban alone and DAP- apixaban
binding in ratios of 1:1, 10:1 and 100:1, as a function of volume (percent)
compared to size (d.nm) as measured by DLS.
[0031] Figure 5 is a graph of DAP alone, fondaparinux alone and DAP-
fondaparinux binding in ratios of 1:1, 10:1 and 100:1, as a function of volume
(percent) compared to size (d.nm) as measured by DLS.
[0032] Figure 6 is a graph of DAP alone, LMWH alone and DAP-LMWH
binding in ratios of 1:1, 1:10 and 100:1, as a function of volume (percent)
compared to size (d.nm) as measured by DLS.
[0033] Figure 7 is a graph of DAP alone, argatroban alone and DAP-argatroban
binding in ratios of 1:1, 10:1, 100:1, and 1000:1, as a function of volume
(percent) compared to size (d.nm) as measured by DLS.
[0034] Figure 8 is a graph of activated partial thromboplastin time (aPTT,
seconds) measured over time (hours) during five hours after subcutaneous
administration of 10 mg of bemiparin (LMWH) to a rat. Four hours into
treatment, the rat received an intravenous dose of 200 mg/kg (100mg) DAP.
[0035] Figure 9 is a graph of activated partial thromboplastin time (aPTT,
seconds) measured over time (hours) after oral administration of PRADAXA®
(dabigatran) to a rat followed by intravenous administration of 200 and
100 mg/kg (100mg and 50 mg) DAP.
[0036] Figure 10 is a graph of activated partial thromboplastin time (aPTT)
measured over time (hours) after subcutaneous administration of unfractionated
heparin (UFH) to a rat followed by intravenous administration of 200 mg/kg
(100 mg) and 400 mg/kg (200 mg) DAP.
[0037] Figure 11 is a graph of aPTT (seconds) measured over time (hours) after
oral administration of 5mg/kg of rivaroxaban to a rat followed by intravenous
administration of 5 mg/kg (2 mg) DAP.
[0038] Figure 12 is a graph of active fondaparinux concentration (µg/mL)
measured over time (minutes after reversal) after a subcutaneous administration
of 5 mg/kg fondaparinux to a rat, followed by intravenous administration of
200 mg/kg DAP (i.e., “reversal”).
[0039] Figure 13 is a graph of aPTT (seconds) measured over time (minutes
after reversal) after oral administration of 15.5 mg/kg PRADAXA® (dabigatran)
to a rat, followed by intravenous administration of 100 mg/kg DAP (i.e.,
“reversal”).
[0040] Figure 14 is a graph of the aPTT time (seconds) for 0, 2, 10, 25, 50, and
100 mg intravenously administered DAP.
[0041] Figure 15 is a graph of blood collected (i.e., cumulative blood loss) over
minutes in a rat tail transection bleeding assay in rats receiving 2 mg
rivaroxaban and 0 mg DAP, 2 mg rivaroxaban and 2.5 mg DAP, 2 mg
rivaroxaban and 12.5 mg DAP, or sham reversal and anticoagulant doses
(“sham”). With groups of three age-matched rats, 12.5 mg of DAP reduced blood
loss to sham dose levels yielding a statistically significant difference (* p<0.05)
from rats receiving rivaroxaban only.
[0042] Figure 16 is a graph of blood collected (i.e., cumulative blood loss) over
minutes in a rat tail transection bleeding assay in rats receiving 1.25 mg
apixaban and 0 mg DAP, 1.25 mg apixaban and 5 mg DAP, 1.25 mg apixaban
and 12.5 mg DAP, or sham reversal and anticoagulant doses (“sham”). With
groups of three age-matched rats, 5 mg and 12.5 mg of DAP reduced blood loss
to sham dose levels yielding a statistically significant difference (*** p<0.01)
from rats receiving apixaban only.
[0043] Figure 17 is a graph of blood collected (i.e., cumulative blood loss) over
minutes in a rat tail transection bleeding assay in rats receiving 1.25 mg
edoxaban and 0 mg DAP, 1.25 mg edoxaban and 12.5 mg DAP, or sham reversal
and anticoagulant doses (“sham”). With groups of three age-matched rats, 12.5
mg of DAP reduced blood loss to sham dose levels yielding a statistically
significant difference (* p<0.05) from rats receiving edoxaban only.
[0044] Figure 18 is a graph of blood collected (i.e., cumulative blood loss) over
minutes in a rat tail transection bleeding assay in rats receiving 15 mg
dabigatran etexilate and 0 mg DAP, 15 mg dabigatran etexilate and 5 mg DAP,
mg dabigatran etexilate and 12.5 mg DAP, or sham reversal and anticoagulant
doses (“sham”). With groups of three age-matched rats, 12.5 mg of DAP reduced
blood loss to sham dose levels yielding a statistically significant difference
(*** p<0.01) from rats receiving dabigatran etexilate only.
[0045] Figure 19 is a graph of aPTT (seconds) measured in freshly drawn
human blood treated ex vivo with 50 micrograms/ml DAP, 0.25 micrograms/ml
rivaroxaban, 50 micrograms/ml DAP and 0.25 micrograms/ml rivaroxaban, or
saline.
[0046] Figure 20 is a graph showing effective anticoagulant concentration
measured by anti-factor Xa activity assay in human plasma treated ex vivo with of
218 µg/L rivaroxaban alone or in combination with 1,250 mg/L DAP, and
459 µg/L rivaroxaban alone or in combination with 6,250 µg/L DAP.
[0047] Figure 21 is a graph showing effective anticoagulant concentration
measured by anti-factor Xa activity assay in human plasma treated ex vivo with
156 µg/L apixaban alone or in combination with 1,156 µg/L DAP, and 313 µg/L
apixaban alone or in combination with 3,125 µg/L DAP.
[0048] Figure 22 is a graph showing effective anticoagulant concentration
measured by anti-factor Xa activity assay in human plasma treated ex vivo with
218 µg/L rivaroxaban, alone or in combination with increasing amounts (1.25,
12.5, 125, and 1,250 µg/L) of DAP.
DETAILED DESCRIPTION OF THE INVENTION
I. Anticoagulant Reversal Agents
[0049] Novel anticoagulant reversal agents are disclosed. The compounds of the
invention include compounds provided herein, as well as the pharmaceutically
acceptable salts thereof.
[0050] Inhibitors of heparin, heparin fragments, fondaparinux and factor Xa or
factor IIa inhibitors (e.g., oral factor Xa or factor IIa inhibitors) have been
developed. The general structure of the anti-coagulant reversal agents of interest
is: R-Z-R’, where R and R’ are positively charged agents at physiologic pH and
can be the same or different molecules and Z is a hydrophobic cyclic or fused
ring compound.
[0051] More specifically, the inhibitor is a compound of the formula (I) or
pharmaceutically acceptable salt thereof:
(I)
wherein:
A is a substituted or unsubstituted aromatic or non-aromatic, carbocyclic or
heterocyclic ring or a linear moiety;
L and L’ are the same or different and are linkers;
X and X’ are the same or different and are absent or are a functional group
that attaches the linker L to M and the linker L’ to M’, respectively;
M and M’ are the same or different and are absent or is a linker that
attaches X to Y and X’ to Y’, respectively; and
Y and Y’ are the same or different and are a moiety containing one or more
cationic atoms or groups or one or more groups that become cationic under
physiological conditions.
[0052] The compounds can be symmetrical or asymmetrical; that is, one or more
of L, L’, X, X’, M, M’, Y, or Y’ can be the same or different. The compounds
can be chiral (i.e., contain one or more chiral centers) or achiral.
[0053] In some embodiments, A is a heterocyclic moiety. In other embodiments,
A is a heterocyclic moiety and L and L’ are a substituted or unsubstituted
alkylene chain. In still other embodiments, A is a heterocyclic moiety, L and L’
are a substituted or unsubstituted alkylene chain, and X and X’ are –NH-C(=O)-.
In still other embodiments, A is a heterocyclic moiety, L and L’ are a substituted
or unsubstituted alkylene chain, X and X’ are –NH-C(=O)-, and M and M’ are a
substituted alkylene chain. As used herein, alkylene chain is a divalent alkelene
moiety that is C to C , preferably C to C in length, and which may be
1 10 3 6
substituted or unsubstituted. Exemplary substituents include alkyl, hydroxyl,
hydroxyl alkyl, amino, amino alkyl, alkoxy, alkyl alkoxy. As used herein, the
term alkyl is C to C , preferably C -C straight chain or branched hydrocarbon.
1 10 1 6
In still other embodiments, A is a heterocyclic moiety, L and L’ are a substituted
or unsubstituted alkylene chain, X is –NH-C(=O)-, M and M’ are a substituted
alkylene chain, and Y and Y’ are a guanidine moiety.
[0054] In some embodiments, A is a non-aromatic, heterocyclic ring, such as
piperazine or diketopiperazine. In other embodiments, A is a linear moiety, such
as a linear diamine or other linear moiety containing reactive functional groups
that can form a bond to X and X’, when present, or Y and Y’. In some
embodiments, the linkers L and L’ are attached to the heteroatoms in the ring A,
such as the two nitrogen atoms in piperazine. In other embodiments, the linker L
and L’ are attached to atoms other than the heteroatoms in the ring, such as
carbon. In particular embodiments, A is a 1,4 or 2,5 disubstituted piperazine
ring. In some embodiments, L and L’ and/or M and M’ are a substituted or
unsubstituted alkylene chains, such as –(CH ) -, where n is an integer from 1-10,
2 n
preferably from 1-6, e.g., 1-3. In particular embodiments, n is 3. In some
embodiments, L and/or M are absent.
[0055] X and X’ are a functional group that attaches the linkers L and L’ to Y
and Y’. Exemplary functional groups include, but are not limited to, esters,
amides, carbonates, and ketones. In particular embodiments, X and X’ are a
functional group that is resistant to simple hydrolysis, such as an amide group.
[0056] Y and Y’ are a moiety that contains one or more atoms or groups that are
cationic or will be cationic under physiological conditions. Examples include
amine and guanidine moieties as well as phosphorous containing moieties, such
as alkyltriphenylphosphonium, tetraphenylphosphonium, tetraphenylarsonium,
tribenzyl ammonium, and phosphonium moieties. Additional cationic moieties
include cationic oligomers and polymers, such as oligo- or polylysine, oligo- or
polyarginine, N-alkylated polyethylene imine, and the like. Other cationic
moieties include delocalized lipophilic cations containing one to three carbimino,
sulfimino, or phosphinimino units as described in Kolomeitsev et al., Tet. Let.,
Vol. 44, No. 33, 5795-5798 (2003).
[0057] In some embodiments, the compound is a piperazine derivative, wherein
the amino acid side chains contain one or more positively charged atoms or atoms
that will be positively charged under physiological conditions. Examples include
diarginine piperazine. Other amino acids that are positively charged or will be
positively charged under physiological conditions can be substituted for arginine.
[0058] “Aromatic”, as used herein, refers to 5membered, preferably 5-, 6-
and 7-membered aromatic, heterocyclic, fused aromatic, fused heterocyclic,
biaromatic, or bihetereocyclic ring systems, optionally substituted. Broadly
defined, “Ar”, as used herein, includes 5-, 6- and 7-membered single-ring
aromatic groups that may include from zero to four heteroatoms, for example,
benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole,
pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl
groups having heteroatoms in the ring structure may also be referred to as “aryl
heterocycles” or “heteroaromatics”. The aromatic ring can be substituted at one
or more ring positions with such substituents as described above, for example,
halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,
amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl,
carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,
heterocyclyl, aromatic or heteroaromatic moieties, --CF , --CN, or the like. The
3
term “Ar” also includes polycyclic ring systems having two or more cyclic rings
in which two or more carbons are common to two adjoining rings (i.e., “fused
rings”) wherein at least one of the rings is aromatic, e.g., the other cyclic ring or
rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles.
Examples of heterocyclic ring include, but are not limited to, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl,
cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3
b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,
isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-
oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl,
pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,
quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-
thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl,
thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl.
[0059] “Heterocycle” or “heterocyclic”, as used herein, refers to a cyclic radical
attached via a ring carbon or nitrogen of a monocyclic or bicyclic ring containing
3-10 ring atoms, and preferably from 5-6 ring atoms, consisting of carbon and
one to four heteroatoms each selected from the group consisting of non-peroxide
oxygen, sulfur, and N(R) wherein R is absent or is H, O, (C )alkyl, phenyl or
1- 4
benzyl, and optionally containing 1-3 double bonds and optionally substituted
with one or more substituents. Examples of heterocyclic ring include, but are not
limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,
benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-
dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,
imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,
3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl,
morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-
oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,
pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-
quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,
thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl and xanthenyl.
[0060] In another embodiment the inhibitor is a compound represented by the
formula II or a pharmaceutically acceptable salt thereof:
(II)
O
O
L' C Y'
Y C L
N M'
M N
H
H
N N
wherein each of L, L′, M, M′, Y and Y′ are as previously described.
[0061] In another embodiment the inhibitor is a compound represented by the
formula III or a pharmaceutically acceptable salt thereof:
O O
(III)
Y C L L' C Y'
M NH N N N M'
H
wherein L, L′, M, M′, Y and Y′ are as previously described.
[0062] In yet another embodiment the inhibitor is a compound represented by the
formula (IV) or pharmaceutically acceptable salt thereof:
G G
(IV)
H H
Y'
Y CH N N CH
N N
(CH ) C (CH ) (CH ) C (CH )
2 2 2 m 2 n
n m
O O
wherein Y and Y′ are as previously described and n is 3 to 5, m is 3 to 6 and G is
selected from –NH and OH. Most preferably, G is amino.
2
[0063] Yet another embodiment the inhibitor is a compound represented by any
of formula II, III or IV and Y and Y′ are independently selected from the group
consisting of
NH
N
H
NH
2 and -NH
2.
[0064] Most preferably G is –NH and Y and Y′ are
2
NH
N
H
NH
2.
[0065] Thus, in one embodiment, the compound of the invention is di-arginine
piperazine (“DAP”), such as the compound of formula V, or a related compound
of formula VI, or pharmaceutically acceptable salts of either compound:
(V)
O
O
H H
N
N
HN NH NN NH NH
2 2
N N
H H
H N
NH
2 2
2-Aminoguanidino-pentanoic acid (3-{4-[3-(2-aminoguanidino-
pentanoylamino)-propyl]-piperazinyl}-propyl)-amide; or
(VI)
O
NH HN
O
HN NH NH HN
2
NH
H N H N NH
2
2
HN
NH
2
2-Aminoguanidino-pentanoic acid {5-[(2-aminoguanidino-
pentanoylamino)-methyl]-piperazinylmethyl}-amide.
[0066] In a specific embodiment, the compound of formula V is a stereoisomer
as depicted in formula VII:
(VII)
O O
NH HN
HN NH N N H N NH
2 2
NH HN
H N NH
2 2 .
[0067] In another specific embodiment, the compound of formula VI is a
stereoisomer as depicted in formula VIII:
(VIII)
O
NH
HN
O
HN NH NH HN
2
NH
H N H N NH
2 2
HN
NH
2
.
[0068] The phrase “pharmaceutically acceptable salt” of a compound as used
herein means a salt that is pharmaceutically acceptable and that possesses the
desired pharmacological activity of the parent compound. Pharmaceutically
acceptable salts include salts of acidic or basic groups present in compounds of
the invention. Pharmaceutically acceptable acid addition salts include, but are
not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate,
citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,
fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and
pamoate (i.e., 1,1'-methylene-bis-(2-hydroxynaphthoate)) salts. Suitable base
salts include, but are not limited to, aluminum, calcium, lithium, magnesium,
potassium, sodium, zinc, and diethanolamine salts.
[0069] The compound of the invention inhibits activity of coagulation inhibitors.
One proposed mechanism of action of the compound of the invention is through
binding negatively charged molecules (e.g., fondaparinux, unfractionated
heparin, LMWH, described herein). Other coagulation inhibitors (e.g., factor IIa
and factor Xa inhibitors such as dabigatran, apixaban, edoxaban, and
rivaroxaban, described herein) also possess negative charges; thus, the compound
of the invention may inhibit these coagulation inhibitors through neutralization of
their negatively charged moieties.
[0070] Another proposed mechanism of action of the compound of the invention
is through weak physical interactions such as hydrogen bonding and hydrophobic
interactions with the coagulation inhibitors. Oral Factor IIa and Xa inhibitors
possess hydrophobic portions, which may cause hydrophobic association with the
compound of the invention, e.g., DAP.
[0071] Thus, in some embodiments, the compounds of the invention contain at
least one cyclic hydrophobic moiety, e.g., one or a combination of aliphatic or
aromatic rings including fused rings. In other embodiments, the compounds of
the invention contain at least one cyclic hydrophobic moiety and a least two
positively charged or partially charged moieties at physiological pH.
[0072] In some embodiments of the invention, one or both arginines of the
compounds of Formulas V and VI (or the compounds of Formulas VII and VIII)
are substituted by one or more positively charged amino acids, their derivatives,
or similarly charged compounds, e.g., lysine, histidine, ornithine. The arginines
in the compounds of Formulas V and VI or positively charged amino acids
substituted for such arginines can be naturally occurring amino acids (i.e., L-
amino acids), their enantiomers (i.e., D-amino acids), or racemic or other
mixtures thereof. “Enantiomers” refer to two stereoisomers of a compound
which are non-superimposable mirror images of one another.
[0073] Stereochemical definitions and conventions used herein generally follow
S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-
Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of
Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic
compounds exist in optically active forms, i.e., they have the ability to rotate the
plane of plane-polarized light. In describing an optically active compound, the
prefixes D and L or R and S are used to denote the absolute configuration of the
molecule about its chiral center(s). The prefixes D and L or (+) and (-) are
employed to designate the sign of rotation of plane-polarized light by the
compound, with (-) or L meaning that the compound is levorotatory. A
compound prefixed with (+) or D is dextrorotatory. For a given chemical
structure, these stereoisomers are identical except that they are mirror images of
one another. A specific stereoisomer may also be referred to as an enantiomer,
and a mixture of such isomers is often called an enantiomeric mixture. A 50:50
mixture of enantiomers is referred to as a racemic mixture or a racemate, which
may occur where there has been no stereoselection or stereospecificity in a
chemical reaction or process. The terms “racemic mixture” and “racemate” refer
to an equimolar mixture of two enantiomeric species, devoid of optical activity.
[0074] In other embodiments of the invention, the compound of the invention
contains at least one cyclic hydrophobic moiety, e.g., one or a combination of
aliphatic and aromatic rings including fused rings. Compounds of interest
contain at least one cyclic hydrophobic moiety and at least two positively charged
or partially charged moieties at physiological pH.
[0075] Special consideration should be given to the design of peptide-based
therapeutic agents, since such agents may cause unwanted and often severe
immunological reactions once administered to a subject. The compound of the
invention is designed to be of sufficiently low molecular weight to minimize
immunogenicity issues. In one embodiment, in order to avoid activation of the
immune response, the compound is designed such that its molecular weight is
less than about 5000 daltons, such as less than or about 1000 daltons, e.g., about
500 daltons. In one embodiment, the molecular weight of the compound is about
512 daltons.
[0076] It is preferable that the compounds of the invention do not bind, or
otherwise interfere with the function of the ERG, a potassium ion channel that
contributes to the electrical conductivity of the heart. Inhibition of this potassium
channel may lead to potentially fatal long QT syndrome, and some otherwise
successful drug candidates have exhibited human ERG binding.
[0077] In addition, it is preferable that the compound of the invention does not
inhibit or serve as substrates for membrane-bound cytochrome p450 (CYP)
enzymes. CYPs are major enzymes involved in drug metabolism, and
modulation of CYP activity may interfere with clearance and metabolism of other
drugs administered to a subject, causing unwanted drug interactions.
[0078] Also preferably, the compounds of the invention do not exhibit
significant plasma protein binding in vitro (e.g., albumin binding). Because the
compounds of the invention are largely unbound to plasma proteins, they exhibit
short activity half-lives minimizing the risk of accumulation-based overdose.
II. Synthesis of Anticoagulant Reversal Agents
[0079] The compounds and their pharmaceutically acceptable salts described
herein are prepared using a variety of methods starting from commercially
available compounds, known compounds, or compounds prepared by known
methods. Exemplary synthetic routes to one of the compounds described herein
(Compound of Formula V, di-arginine piperazine, “DAP”) are included in the
schemes below. The schemes below are also applicable to the DAP stereoisomer
compound of Formula VII by selecting the appropriate stereoisomeric starting
compounds. Other compounds of the invention may be synthesized following a
similar synthetic scheme. It is understood by those skilled in the art that the order
of steps shown herein may be changed to accommodate functionality in the target
molecule. It is also understood by those skilled in the art that various protection
and deprotection steps may be required for synthesis. The need for protection
and deprotection, and the selection of appropriate protecting groups are found, for
example, in Greene and Wuts, Protecting Groups in Organic Synthesis, Second
Edition, John Wiley & Sons (1991), which is incorporated herein by reference in
its entirety.
[0080] In some embodiments of the present invention, the protecting group is
tertiary butyloxycarbonyl group (Boc). In other embodiments of the present
invention, the protecting group is 2,2,4,6,7-Pentamethyldihydrobenzofuran
sulfonyl group (Pbf). In another embodiment, amino acid protecting group may
be, but is not limited to, 2,2,5,7,8-pentamethyl-chromansulphonyl (PMC).
[0081] Protecting groups may be removed by a variety of routes. Removal of
protecting group comprises, e.g., treating protected compound with
trifluoroacetic acid (TFA), aqueous HCl, or heating in acetic acid. Because
removal of protecting groups, e.g., removal of protecting groups under acidic
conditions, can result in production of cationic species that can alkylate the
functional groups on the peptide chain, scavengers may be added during the
deprotection step to react with any of the free reactive species. Examples of
scavengers include, but are not limited to, water, anisol derivatives and thiol
derivatives. Thus, in one embodiment, removal of protecting groups comprises
treating protected compound with TFA and a scavenger (e.g., TFA and water).
[0082] Various solvents, e.g., organic solvents, may be used in the steps of the
synthesis. Appropriate solvents include, but are not limited to, dimethyl
sulfoxide, dimethylformamide (DMF), tetrahydrofuran, methanol, ethanol,
methylene chloride, toluene, and acetone. In some embodiments, the solvent is
DMF.
[0083] Suitable acid binding agents may be used in the steps of the synthesis.
These include, but are not limited to, organic bases, such as, for example,
pyridine, triethylamine, triethanolamine, 1,8-diazabicyclo[5.4.0]undecene
(DBU), and diisopropylethylamine (DIEA); and inorganic bases, such as, for
example, sodium hydride, potassium carbonate, and sodium carbonates. In some
embodiments, the acid binding agent is DIEA.
[0084] Synthesis may include peptide coupling reagents. Peptide coupling
reagents may include, but are not limited to, 1-ethyl(3-dimethylaminopropyl)
carbodiimide (EDC), N-Hydroxybenzotriazole (HOBt), carbonyldiimidazole
(CDI), dicyclohexylcarbodiimide (DCC), active N-hydroxysuccinamide (OSu)
ester, O-Benzotriazole-N,N,N’,N’-tetramethyl-uronium-hexafluoro-phosphate
(HBTU), and combinations thereof. In one embodiment, the peptide coupling
reagent is HBTU. In another embodiment, the peptide coupling reagent is
EDC/HOBt. In yet another embodiment, the peptide coupling reagent is an
active OSu ester.
[0085] Additionally, the synthesis may include a step in which a crude product is
purified, e.g., by column chromatography. The desired products of each step or
series of steps may be separated and/or purified to the desired degree of
homogeneity by the techniques common in the art. Typically such separations
involve multiphase extraction, crystallization from a solvent or solvent mixture,
distillation, sublimation, or chromatography. Chromatography can involve any
number of methods including, for example: reverse-phase and normal phase; size
exclusion; ion exchange; high, medium, and low pressure liquid chromatography
methods and apparatus; small scale analytical; simulated moving bed (SMB) and
preparative thin or thick layer chromatography, as well as techniques of small
scale thin layer and flash chromatography.
[0086] In one scheme, the compound of Formula V (DAP)
(V)
O O
H H
N N
HN NH NN NH NH
2 2
N N
H H
H N
NH
2
2
is synthesized by reacting excess equivalents (e.g., at least about two equivalents)
of compound 1
O
OH
HN NH P
1
N
H
P N
2
H
(1)
with one equivalent of compound 2
H N NH
2 2
NN
(2),
in the presence of a peptide coupling reagent, to obtain a compound 3
O O
H
H
N
N
HN NH P
NN P NH NH
1
1
N
N
H H
P N N P
2 2
H H
(3),
wherein P1 is a protecting group and P2 is a protecting group or is a hydrogen.
[0087] In one embodiment, the peptide coupling reagent is HBTU, EDC/HOBt,
or an active OSu ester. In one embodiment, the protecting group P1 is Boc. In
another embodiment, the protecting group P2 is Pbf. In a different embodiment,
the protecting group P1 is Boc and P2 is a hydrogen.
[0088] Subsequently, 3 may be purified. This purification may involve various
column chromatography methods known in the art.
[0089] Protecting groups of 3 may be removed by a variety of methods known in
the art in order to obtain the compound of Formula V. Deprotection can be
achieved by, e.g., removal of protecting groups using trifluoroacetic acid (TFA)
and water, TFA and water or another scavenger, including, but not limited to
aqueous HCl, or heating in acetic acid.
[0090] The compound may be further purified using a column chromatography
method, such as ion exchange chromatography with salt buffers or preparative
HPLC with trifluoroacetic acid or acetic acid as a buffer.
[0091] In a more specific scheme, the coupling involved reacting compound 1,
wherein P1 was Boc and P2 was a hydrogen (depicted as Boc-Arg-OH·HCl
below), with compound 2 as depicted below:
NH
2
N
EDC (2.6 eq)
Boc-Arg-OH. HCl
+
HOBt (2.6 eq)
(2.2 eq) N
95%
H N
2
(1 eq)
H
N
Boc-Arg N
N Arg-Boc
N
H
The resultant crude product was more than 95% pure by thin layer
chromatography (TLC).
[0092] Subsequently, the deprotection step was carried out as depicted below:
H
N
Boc-Arg N
TFA / H O
2
N Arg-Boc
(95 / 5)
N
H
H
N
H-Arg N
N Arg-H
N
H .2TFA
[0093] The deprotected product was purified by preparative HPLC using 1%
acetic acid buffer. Product purity of ≥98% was observed. Residual TFA was
removed by low quantity of DOWEX resin. The molecular weight of DAP (the
compound of Formula V) is 512.4, and the compound synthesized according to
the above scheme exhibited the following primary peak by mass spectroscopy:
+
[M+H] =513.4.
III. Pharmaceutical Compositions
[0094] Pharmaceutical compositions comprising the compounds described
herein are provided. Such a composition may contain, in addition to the
compound of the invention, a pharmaceutically acceptable carrier or excipient.
The term “pharmaceutically acceptable” means a nontoxic material that is
compatible with the physical and chemical characteristics of the active ingredient
and does not interfere with the effectiveness of the biological activity of the
active. The compositions may contain various diluents, fillers, salts, buffers,
stabilizers, solubilizers, and other materials well known in the art. The
characteristics of the carrier will depend on the route of administration, and are
generally well known in the art.
[0095] The pharmaceutical composition of the invention may be adapted for
enteral administration – administration of the composition, wherein the
composition is absorbed through the digestive tract, e.g., oral ingestion, rectal
administration. In other embodiments, the pharmaceutical composition of the
invention may be adapted for parenteral administration – administration of the
composition, wherein the composition is introduced via a route other than
digestive tract, e.g., intravenous, subcutaneous, cutaneous, nasal, pulmonary,
vaginal, buccal route.
[0096] Suitable pharmaceutical compositions, e.g., compositions for oral
administration, may be prepared as described in references such as
“Pharmaceutical dosage form tablets”, eds. Liberman et. al. (New York, Marcel
Dekker, Inc., 1989), “Remington – The science and practice of pharmacy”, 20th
ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, and “Pharmaceutical
th
dosage forms and drug delivery systems”, 6 Edition, Ansel et.al., (Media, PA:
Williams and Wilkins, 1995), incorporated herein by reference, which provide
information on carriers, materials (e.g., coating materials), equipment and process
for preparing tablets and capsules and delayed release dosage forms of tablets,
capsules, and granules.
[0097] Examples of suitable coating materials include, but are not limited to,
cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and
hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate,
acrylic acid polymers and copolymers, and methacrylic resins that are
®
commercially available under the trade name Eudragit (Roth Pharma,
Westerstadt, Germany), Zein, shellac, and polysaccharides. Additionally, the
coating material may contain conventional carriers such as plasticizers, pigments,
colorants, glidants, stabilization agents, pore formers and surfactants.
[0098] Optional pharmaceutically acceptable excipients present in the drug-
containing tablets, beads, granules or particles include, but are not limited to,
diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants.
[0100] Diluents, also termed "fillers," are typically necessary to increase the bulk
of a solid dosage form so that a practical size is provided for compression of tablets
or formation of beads and granules. Suitable diluents include, but are not limited
to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol,
sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch,
hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide,
magnesium aluminum silicate and powder sugar.
[0101] Binders are used to impart cohesive qualities to a solid dosage formulation,
and thus ensure that a tablet or bead or granule remains intact after the formation of
the dosage forms. Suitable binder materials include, but are not limited to, starch,
pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose
and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as
acacia, tragacanth, sodium alginate, cellulose, including
hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and
veegum, and synthetic polymers such as acrylic acid and methacrylic acid
copolymers, methacrylic acid copolymers, methyl methacrylate copolymers,
aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and
polyvinylpyrrolidone.
[0102] Lubricants are used to facilitate tablet manufacture. Examples of suitable
lubricants include, but are not limited to, magnesium stearate, calcium stearate,
stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
[0103] Disintegrants are used to facilitate dosage form disintegration or "breakup"
after administration, and generally include, but are not limited to, starch, sodium
starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose,
hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or
cross linked polymers, such as cross-linked PVP (Polyplasdone XL from GAF
Chemical Corp).
[0104] Stabilizers are used to inhibit or retard drug decomposition reactions which
include, by way of example, oxidative reactions.
[0105] Surfactants may be anionic, cationic, amphoteric or nonionic surface active
agents. Suitable anionic surfactants include, but are not limited to, those containing
carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include
sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl
sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium
sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium
sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl
sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not
limited to, quaternary ammonium compounds such as benzalkonium chloride,
benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium
chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants
include ethylene glycol monostearate, propylene glycol myristate, glyceryl
monostearate, glyceryl stearate, polyglyceryloleate, sorbitan acylate, sucrose
acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate,
polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether,
®
polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer 401,
stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
Examples of amphoteric surfactants include sodium N-dodecyl-.beta.-alanine,
sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine
and lauryl sulfobetaine.
[0106] Pharmaceutical compositions of the invention may be designed to provide
delayed, sustained, pulsatile or other modified release.
[0107] If desired, the tablets, beads granules or particles may also contain minor
amount of nontoxic auxiliary substances such as wetting or emulsifying agents,
dyes, pH buffering agents, and preservatives.
[0108] Bioadhesive formulations may also be utilized to enhance uptake or
modify release. Such formulations are known in the art. See, for example, US
Patent Application No. 20060045865 by Jacob, incorporated herein by reference.
[0109] Pharmaceutical compositions adapted for delivery via nasal or pulmonary
administration may also be useful. Aerosols for the delivery of therapeutic agents
to the respiratory tract have been described, for example, Adjei, A. and Garren, J.
Pharm. Res., 7: 565-569 (1990); and Zanen, P. and Lamm, J.-W.J. Int. J. Pharm.,
114: 111-115 (1995). The respiratory tract encompasses the upper airways,
including the oropharynx and larynx, followed by the lower airways, which include
the trachea followed by bifurcations into the bronchi and bronchioli. The upper
and lower airways are called the conducting airways. The terminal bronchioli then
divide into respiratory bronchioli which then lead to the ultimate respiratory zone,
the alveoli, or deep lung. Gonda, I. "Aerosols for delivery of therapeutic and
diagnostic agents to the respiratory tract," in Critical Reviews in Therapeutic Drug
Carrier Systems, 6:273-313 (1990). The deep lung, or alveoli, is the primary
target of inhaled therapeutic aerosols for systemic drug delivery.
[0110] Drugs administered by inhalation may come as liquid aerosol formulations.
[0111] For injectable compositions (e.g., intravenous compositions), the carrier is
distilled sterile water, saline, buffered saline, or another pharmaceutically
acceptable excipient for injection. Additives may include preservatives and acids
or base to adjust pH, to alter solubility or uptake.
[0112] In one embodiment, wherein the pharmaceutical composition comprises
the DAP compound of formula V (or its stereoisomer of formula VII) and the
composition is adapted for parenteral administration in an injection, the compound
is dissolved in water with appropriate tonicity and molality modifiers (such as
phosphate buffered saline). DAP is water-soluble at greater than 100 mg/ml. In the
one embodiment, DAP is adapted as a sterile solution for IV administration. In
one aspect, the molality of the pharmaceutical composition in which DAP is
adapted for IV administration is adjusted to 290 mOsm/L with sodium chloride,
and the pH is adjusted to 7.4 with sodium hydroxide. Preferably the
pharmaceutical composition is administered as an intravenous bolus by slow push.
IV. Methods of Use
[0113] Described is a method of completely or partially reversing an anticoagulant
effect of a coagulation inhibitor comprising administering to a subject in need
thereof a therapeutically effective amount of a compound of the invention (e.g., a
compound of formula I, II, III, IV, V, VI, VII, or VIII) or pharmaceutically
acceptable salt thereof. Also described is a method of promoting coagulation in a
subject in need thereof, wherein the subject is receiving a coagulation inhibitor,
comprising administering to the subject a therapeutically effective amount of a
compound of the invention or a pharmaceutically acceptable salt thereof. In
addition, described is a method of neutralizing or inhibiting a coagulation inhibitor
comprising administering to a subject in need thereof a therapeutically effective
amount of a compound of the invention or a pharmaceutically acceptable salt
thereof.
[0114] As used herein, coagulation inhibitor (also referred to herein as
anticoagulant) is a molecule that inhibits coagulation process. Exemplary
coagulation inhibitors include, but are not limited to, antithrombin activators (e.g.,
unfractionated heparin and LMWH), factor IIa inhibitors, and factor Xa inhibitors.
[0115] Heparin: Heparin is a naturally occurring mucopolysaccharide that acts in
the body as an antithrombin co-factor to prevent intravascular clotting. The
substance is produced by basophils and mast cells, which are found in large
numbers in the connective tissue surrounding capillaries, particularly in the lungs
and liver. In the form of sodium salt, heparin is used therapeutically as an
anticoagulant.
[0116] Low Molecular Weight Heparin: Low Molecular Weight Heparin
(LMWH) is made from heparin using various methods of depolymerization,
including oxidative depolymerization with hydrogen peroxide, used in the
manufacture of ardeparin (NORMIFLO®); deaminative cleavage with isoamyl
nitrite, used in the manufacture of certoparin (SANDOPARIN®); alkaline beta-
eliminative cleavage of the benzyl ester of heparin, used in the manufacture of
enoxaparin (LOVENOX® and CLEXANE®); oxidative depolymerization with
2+
Cu and hydrogen peroxide, used in the manufacture of parnaparin (FLUXUM®);
beta-eliminative cleavage by the heparinase enzyme, used in the manufacture of
tinzaparin (INNOHEP® and LOGIPARIN®); deaminative cleavage with nitrous
acid, used in the manufacture of dalteparin (FRAGMIN®), reviparin
(CLIVARIN®) and nadroparin (FRAXIPARIN®), which results in the formation
of an unnatural anhydromannose residue at the reducing terminal of the
oligosaccharides produced. This can subsequently be converted to
anhydromannitol using a suitable reducing agent. Both chemical and enzymatic
beta-elimination result in the formation of an unnatural unsaturated uronate residue
(UA) at the non-reducing terminal.
[0117] Summary of anticoagulant activities of several LMWHs is presented in
Table 1.
Table 1: Molecular weight (MW) data and anticoagulant activities of currently
available LMWH products.
LMWH Average molecular weight Ratio anti-Xa/anti-IIa activity
BEMIPARIN 3600 9.7
CERTOPARIN 5400 2.4
DALTEPARIN 6000 2.5
ENOXAPARIN 4500 3.9
NADROPARIN 4300 3.3
PARNAPARIN 5000 2.3
REVIPARIN 4400 4.2
TINZAPARIN 6500 1.6
Adapted from Gray E. et al., Thromb Haemost, 99: 807–818 (2008).
[0118] Clinically, LMWH (average molecular weight of about 4.5 kDa) differs
from heparin (i.e., "unfractioned heparin"; average molecular weight of about
kDa) in a variety of ways: (a) LMWH requires less frequent subcutaneous
dosing for postoperative prophylaxis of venous thromboembolism; (2) LMWH
requires once or twice daily subcutaneous injection in patients treated for venous
thromboembolism and unstable angina instead of intravenous infusion required
with heparin; (3) LMWH requires no monitoring of the aPTT coagulation
parameter; (4) LMWH poses a lower risk of bleeding; (5) long term use of LMWH
poses a lower risk of osteoporosis; and (6) LMWH poses a lower risk of heparin-
induced thrombocytopenia (a potential side effect of heparin administration).
However, the anticoagulant effects of heparin are typically reversible with
protamine sulfate, while protamine's effect on LMWH is limited. In addition,
LMWH has less effect on thrombin (Factor IIa) activity compared to heparin,
while both LMWH and heparin have a similar effect on Factor Xa activity.
[0119] Thrombin and Other Factor IIa or Xa Inhibitors: Examples of thrombin
(Factor IIa) and factor Xa inhibitors include anticoagulants such as dabigatran
(PRADAXA®), rivaroxaban (XARELTO®), apixaban (ELIQUIS®), edoxaban
(LIXIANA®), fondaparinux (ARIXTRA®), and argatroban (ARGATROBAN®).
[0120] The chemical name for oral anticoagulant PRADAXA®, dabigatran
etexilate mesylate, a direct thrombin inhibitor, is β-Alanine, N-[[2-[[[4-
[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]methyl-1H-
benzimidazolyl]carbonyl]-Npyridinyl-,ethyl ester, methanesulfonate.
Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors.
Because thrombin (Factor IIa, serine protease) enables the conversion of fibrinogen
into fibrin during the coagulation cascade, its inhibition prevents the development
of a thrombus.
[0121] Rivaroxaban, a factor Xa inhibitor, is the active ingredient in
XARELTO®, and has the chemical name 5-Chloro-N-({(5S)oxo[4-(3-oxo
morpholinyl)phenyl]-1,3-oxazolidinyl}methyl)thiophenecarboxamide.
Rivaroxaban is a pure (S)-enantiomer. XARELTO® is an orally bioavailable
factor Xa inhibitor that selectively blocks the active site of factor Xa and does not
require a cofactor (such as Anti-thrombin III) for activity.
[0122] Apixaban or ELIQUIS® is 1-(4-methoxyphenyl)oxo[4-
(2-oxopiperidinyl)phenyl]-4,5-dihydropyrazolo[5,4-c]pyridine-
3-carboxamide. It is an orally administered direct factor Xa inhibitor approved in
Europe and presently undergoing phase III trials in the U.S. for the prevention of
venous thromboembolism.
[0123] Edoxaban or LIXIANA® is N'-(5-chloropyridinyl)-N-[(1S,2R,4S)
(dimethylcarbamoyl)[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine
carbonyl)amino]cyclohexyl]oxamide. Edoxaban is a direct factor Xa inhibitor, and
it has been approved in Japan for use in preventing venous thromboembolism.
[0124] ARIXTRA® is fondaparinux sodium. It is a synthetic and specific
inhibitor of activated Factor X (Xa). Fondaparinux sodium is methyl Odeoxy-
6-O-sulfo(sulfoamino)-α-D-glucopyranosyl-(1→4)-O-β-D-glucopyra-
nuronosyl-(1→4)-Odeoxy-3,6-di-O-sulfo(sulfoamino)-α-D-glucopyranosyl-
(1→4)-OO-sulfo-α-L-idopyranuronosyl-(1→4)deoxyO-sulfo
(sulfoamino)-α-D-glucopyranoside, decasodium salt. The molecular formula of
fondaparinux sodium is C H N Na O S and its molecular weight is 1728. The
31 43 3 10 49 8
structural formula is provided below:
[0125] The antithrombotic activity of fondaparinux sodium is the result of
antithrombin III (ATIII)-mediated selective inhibition of Factor Xa. By selectively
binding to ATIII, fondaparinux sodium potentiates (about 300 times) the innate
neutralization of Factor Xa by ATIII. Neutralization of Factor Xa interrupts the
blood coagulation cascade and thus inhibits thrombin formation and thrombus
development. Fondaparinux sodium does not inactivate thrombin (activated Factor
II) and has no known effect on platelet function. At the recommended dose,
fondaparinux sodium does not affect fibrinolytic activity or bleeding time. The
pharmacodynamics/pharmacokinetics of fondaparinux sodium are derived from
fondaparinux plasma concentrations quantified via anti-factor Xa activity. Only
fondaparinux can be used to calibrate the anti-Xa assay. (The international
standards of heparin or LMWH are not appropriate for this use.) As a result, the
activity of fondaparinux sodium is expressed as milligrams (mg) of the
fondaparinux calibrator. The anti-Xa activity of the drug increases with increasing
drug concentration, reaching maximum values in approximately three hours.
Fondaparinux sodium administered by subcutaneous injection is rapidly and
completely absorbed (absolute bioavailability is 100%). In patients undergoing
treatment with fondaparinux sodium injection 2.5 mg, once daily, the peak steady-
state plasma concentration is, on average, 0.39 to 0.50 mg/L and is reached
approximately 3 hours post-dose. In these patients, the minimum steady-state
plasma concentration is 0.14 to 0.19 mg/L. In patients with symptomatic deep vein
thrombosis and pulmonary embolism undergoing treatment with fondaparinux
sodium injection 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg),
and 10 mg (body weight >100 kg) once daily, the body-weight-adjusted doses
provide similar mean steady-state peaks and minimum plasma concentrations
across all body weight categories. The mean peak steady-state plasma
concentration is in the range of 1.20 to 1.26 mg/L. In these patients, the mean
minimum steady-state plasma concentration is in the range of 0.46 to 0.62 mg/L.
[0126] ARGATROBAN® is a synthetic direct thrombin (Factor IIa) inhibitor,
derived from L-arginine. The chemical name for ARGATROBAN® is 1-[5-
[(aminoiminomethyl) amino]oxo[[(1,2,3,4-tetrahydromethyl
quinolinyl)sulfonyl]amino]pentyl]methylpiperidinecarboxylic acid,
monohydrate. The molecular formula of ARGATROBAN® is C H N O S•H O.
23 36 6 5 2
Its molecular weight is 526.66. ARGATROBAN® is a direct thrombin inhibitor
that reversibly binds to the thrombin active site. ARGATROBAN® does not
require the co-factor antithrombin III for antithrombotic activity.
ARGATROBAN® is administered by injection, and it exerts its anticoagulant
effects by inhibiting thrombin-catalyzed or thrombin-induced reactions, including
fibrin formation; activation of coagulation factors V, VIII, and XIII; activation of
protein C; and platelet aggregation.
[0127] An anticoagulant effect is any effect of a coagulation inhibitor (e.g.,
heparin, LMWH, Factor Xa inhibitor, Factor IIa inhibitor) that results from its
blockage of the propagation of the coagulation cascades. Nonlimiting examples of
anticoagulation effects include upregulation of antithrombin activity, decreased
Factor Xa activity, decreased Factor IIa activity, increased blood loss, and any
other conditions wherein the activity or concentrations of clotting factors are
altered in such a way as to inhibit blood clot formation.
[0128] Activity of a coagulation inhibitor (i.e., its anticoagulant effects) may be
measured by a variety of methods, including but not limited to a chromogenic anti-
factor Xa activity assay, activated partial thromboplastin time assay, prothrombin
time, bleeding assay (e.g., rat tail bleeding assay), thromboelastography, thrombin
generation assay, dilute Russel’s viper venom time, ecarin clotting time, kaolin
clotting time, International Normalized Ratio (INR), fibrinogen testing (Clauss),
thrombin time (TCT), mixing time, and euglobulin lysis time. These methods aid
in determining various anticoagulation parameters, and are known to those skilled
in the art. Thus, in some embodiments, anticoagulation can be monitored by one
or a combination of the above listed assays.
[0129] The anti-factor Xa assay directly measures anti-factor Xa activity. The
methodology behind an anti-factor Xa assay is that patient plasma is added to a
known amount of excess factor Xa and excess antithrombin. If a factor Xa
inhibitor is present in the patient plasma, it will reduce the enzymatic activity of
factor Xa. The amount of residual factor Xa is inversely proportional to the
amount of anti-Xa agent in the plasma. The amount of residual factor Xa is
detected by adding a chromogenic substrate that mimics the natural substrate of
factor Xa, making residual factor Xa cleave it, releasing a colored compound that
can be detected by a spectrophotometer. Antithrombin deficiencies in the patient
do not affect the assay, because excess amounts of antithrombin are provided in the
reaction. Results are given in anticoagulant concentration in units/mL of antifactor
Xa, such that high values indicate high levels of anticoagulation and low values
indicate low levels of anticoagulation.
[0130] The activated partial thromboplastin time (aPTT) assay is an assay that
measures how long it takes for the blood to clot. Blood samples are collected for
direct measurement or in tubes with oxalate and citrate to arrest coagulation by
calcium until the assay can be performed. In the assay, a phospholipid, an
activator (silica, celite, kaolin, ellagic acid, etc.), and calcium are mixed into the
plasma to induce coagulation. The assay measures the time until a thrombus (clot)
forms.
[0131] Rat tail bleeding assay or rat tail transection assay is an assay that measures
blood loss, e.g., blood loss after drug administration. In one embodiment, where
the effect of the compound of the invention (e.g., DAP) is being tested, at the
Tmax of the anticoagulant, DAP is administered intravenously. After 20 minutes,
rat tails are transected approximately 1 mm from the tip, placed in room
temperature saline, and blood is collected for 30 minutes and weighed.
[0132] Assays used to measure activity of coagulation inhibitors maybe used in
the laboratory or in the clinic to measure reversal of an anticoagulant effect of a
coagulation inhibitor, e.g., reversal of an anticoagulant effect of a coagulation
inhibitor due to administration of a pharmaceutical composition comprising a
compound of the invention. Thus, in one embodiment, the assays are utilized to
measure complete or partial reversal of an anticoagulant effect of a coagulation
inhibitor (such as heparin, LMWH, Factor IIa inhibitor, and Factor Xa inhibitor).
[0133] A complete reversal of an anticoagulant effect of a coagulation inhibitor
occurs upon neutralization of the anticoagulant activity. In one embodiment, a
complete reversal of an anticoagulant effect of a coagulation inhibitor, as measured
by the anti-Xa activity assay, occurs when anticoagulant concentration is brought
below the minimum effective concentration (MEC) for anticoagulation. MEC, as
used herein, is a lowest amount of the drug (e.g., coagulation inhibitor) required for
therapeutic effect. In another embodiment, a complete reversal of an anticoagulant
effect of a coagulation inhibitor, as measured by the aPTT assay, occurs when the
aPTT returns within about 10% of baseline. A baseline, as used herein, refers to
aPTT in the absence of coagulation inhibitors.
[0134] In many cases, anticoagulation will still be desired, but to a lesser degree.
Thus, a partial reversal of an anticoagulant effect of a coagulation inhibitor will be
indicated. Partial reversal of an anticoagulant effect of a coagulation inhibitor, as
measured by the anti-Xa activity assay, occurs when the anticoagulant
concentration is brought below the anticoagulant concentration in the absence of an
anticoagulation reversal agent (e.g., a compound of the invention), but remains
above the MEC for anticoagulation. Thus, in some embodiments, partial reversal
of an anticoagulation effect of coagulation inhibitors occurs when the
concentration of anticoagulant is lower than about four times the MEC, preferably
about twice the MEC, more preferably less than about twice the MEC (e.g., at
about the MEC). Partial reversal of an anticoagulant effect of coagulation
inhibitor, as measured by aPTT assay, occurs when aPPT is reduced below the
measurement in the absence of an anticoagulation reversal agent (e.g., a compound
of the invention) but above the baseline. Thus, in other embodiments, partial
reversal of an anticoagulation effect of coagulation inhibitors occurs when the
aPTT measurement is reduced below about four times the baseline, preferably
about twice the baseline, more preferably less than about twice the baseline.
Generally, the extent and duration of anticoagulation reversal is determined by the
physician or veterinarian.
[0135] As used herein, “subject in need thereof” is a subject in need of either acute
or planned reversal of anticoagulation, e.g., a subject suffering from anticoagulant
overdose, a subject suffering from hemorrhage (e.g., trauma-induced hemorrhage
or spontaneous hemorrhage in the GI tract or elsewhere), a subject requiring
planned surgical intervention, a subject undergoing an invasive or non-invasive
procedure requiring a biopsy, a subject undergoing a procedure wherein a
procedural error may risk hemorrhage if the subject remains anticoagulated, a
subject requiring spinal or epidural anesthesia. “Subject in need thereof” may be a
patient in whom the presence of a direct factor inhibitor (Factor Xa, Factor IIa
and/or antithrombin) is producing or is likely to produce bleeding effects. Thus,
“subject in need thereof” may be a subject receiving anticoagulation therapy (e.g.,
subject receiving heparin, LMWH, Factor IIa inhibitor, or Factor Xa inhibitor) for,
e.g., stroke prevention, cardiac surgical and diagnostic procedures, cardiac
arrhythmias, deep vein thrombosis (DVT) prevention, pulmonary embolism,
general prevention of the formation of pathologic blood clots.
[0136] “Subject in need thereof,” as used herein, is an animal. “Subject in need
thereof” includes, without limitation, a human, mouse, rat, guinea pig, dog, cat,
horse, cow, pig, monkey, chimpanzee, baboon, or rhesus monkey. In one
embodiment, “subject in need thereof” is a mammal. In another embodiment,
“subject in need thereof” is a human.
[0137] As used herein, “therapeutically effective amount” refers to an amount of
an anticoagulation reversal agent (e.g., a compound of the invention described
herein), which is effective, upon single or multiple dose administration (e.g., bolus
and/or maintenance doses) to a subject, in neutralizing or inhibiting (completely or
partially reversing) an anticoagulant effect of a coagulation inhibitor or in
promoting coagulation.
[0138] In one aspect, a therapeutically effective amount is a dose of an
anticoagulation reversal agent that is between 0.01 and 10,000 times the
anticoagulant dose by weight. In another aspect, the anticoagulation reversal agent
is administered at a dose mass ratio of between about 1:1 and 1000:1 of the
anticoagulation reversal agent to anticoagulant, e.g., 100:1 of the anticoagulation
reversal agent to anticoagulant, such as 10:1 of anticoagulation reversal agent to
anticoagulant. In one embodiment of the present method, a therapeutically
effective amount of the anticoagulation reversal agent may be administered by
subcutaneous, intramuscular, or intravenous route of administration. For example,
it may be administered intravenously as a sterile solution. In another embodiment,
a therapeutically effective amount of the anticoagulation reversal agent is
administered by oral, nasal, or pulmonary route, or to a mucosal region (mouth,
rectum, or vagina).
[0139] The therapeutically effective amount of the anticoagulation reversal agent
(i.e., the compound of the invention) will typically range from about 0.001 mg/kg
to about 1 g/kg of body weight per day; in another embodiment, from about
0.01 mg/kg to about 600 mg/kg body weight per day; in another embodiment, from
about 0.01 mg/kg to about 250 mg/kg body weight per day; in another
embodiment, from about 0.01 mg/kg to about 400 mg/kg body weight per day; in
another embodiment, from about 0.01 mg/kg to about 200 mg/kg of body weight
per day; in another embodiment, from about 0.01 mg/kg to about 100 mg/kg of
body weight per day; in one embodiment, from about 0.01 mg/kg to about 25
mg/kg body weight per day; in another embodiment, from about 0.1 mg/kg to
about 10 mg/kg body weight per day; in another embodiment, from about
0.001 mg/kg to about 100 mg/kg of body weight per day; in another embodiment,
from about 0.001 mg/kg to about 10 mg/kg of body weight per day; and in another
embodiment, from about 0.001 mg/kg to about 1 mg/kg of body weight per day.
Standard coagulation assays (as those described herein) and other in vitro assays
can be used to determine the therapeutically effective amount.
[0140] In some embodiments, the compound of the invention may be co-
administered with at least one additional therapeutic agent. In one embodiment,
the at least one additional therapeutic agent may be vitamin K, which is typically
used to correct clotting deficiencies induced by warfarin compounds.
[0141] Also described is a diagnostic assay for determining the anticoagulant
concentration in the blood. As shown in Example 13 below, DAP demonstrates a
dose-responsive trend in reversing rivaroxaban ex vivo in human plasma using a
510k-cleared anti-factor Xa chromogenic assay. Thus, the compound of the
invention, e.g., DAP, can be used in a diagnostic assay to determine the
concentration of an anticoagulant, e.g., a Factor Xa inhibitor, in the blood. In such
an assay, the compound of the invention, e.g., DAP, can be used either in
conjunction with the currently available kit reagents or as a direct binding substrate
replacing synthetic factors present in currently available kits. In one embodiment,
the diagnostic assay may comprise the compound of the invention (e.g., DAP) as a
binding substrate, wherein the compound of the invention binds an anticoagulant in
a blood sample, and the residual activity of the clotting factor (e.g., Factor Xa) is
quantified to determine the concentration of the anticoagulant in the sample. In
another embodiment, the diagnostic assay may comprise the compound of the
invention (e.g., DAP) conjugated to magnetic microparticles, wherein the
compound of the invention can bind an anticoagulant in a blood sample in order to
either remove the anticoagulant from the sample or to concentrate it. The DAP-
based chromogenic or point of care assay described herein can aid in the
determination of anticoagulant levels in subjects, which is currently a significant
clinical unmet need since current diagnostics cannot determine blood
concentrations of direct inhibitors with high accuracy.
[0142] Additionally, described is an assay, e.g., a chromogenic assay, to determine
the concentration of the compound of the invention, e.g., DAP, required to reverse
the anticoagulant present in the blood. In one embodiment, the assay uses DAP as
a direct binding agent for various anticoagulants.
[0143] Also described is an assay, e.g., a chromogenic assay, to determine the
amount of the compound of the invention, e.g., DAP, in the blood. Such assay
may utilize predetermined concentrations of an anticoagulant.
[0144] Also described is a diagnostic kit that incorporates a diagnostic assay
described herein above. Thus, in one embodiment, the kit is used for determining
the anticoagulant concentration in the blood. The kit may contain other
components, packaging, instructions, reagents, and/or other material to aid in the
determination of anticoagulant (e.g., Factor Xa inhibitor) or DAP concentration
and to aid in the use of the kit. Additionally, the kit may be used to determine if
there is a combination of warfarin and another anticoagulant as warfarin will be
unaffected by the compound of the invention, while other anticoagulants will be
reversed.
[0145] As demonstrated in the following examples, a compound of the invention
(e.g., DAP) is capable of binding heparin, inactivating it in vivo. Thus, in addition
to its effects on coagulation, a compound of the invention may also be used to
deprive tissues of the biochemical activities of heparin. For example, other
heparin-binding molecules have demonstrated the ability to reduce fibroblast
growth factor (FGF), epidermal growth factor (EGF), vascular endothelial growth
factor (VEGF), and other heparin binding growth factors. VEGF and FGF
deprivation has been shown useful in anti-cancer therapy, making compounds of
the invention possible candidates for the treatment of cancer. Therefore, in one
embodiment, described is a method for treating, preventing, or ameliorating a
cancer in a subject, comprising administering to a subject a therapeutically
effective amount of a compound of the invention or a pharmaceutically acceptable
salt thereof.
[0146] As demonstrated in the examples, one compound of the invention, DAP,
bound XARELTO®, ELIQUIS®, ARIXTRA® and LMWH in vitro as measured
by dynamic light scattering (DLS). DAP reversed subcutaneously administered
ARIXTRA® and LMWH in vivo. DAP reversed XARELTO®, ELIQUIS®,
PRADAXA®, LIXIANA®, unfractionated heparin and bemiparin in vivo. DAP
intravenously administered at 100mg/kg, 250mg/kg and 400mg/kg doses in rats
showed no adverse effect. DAP was orally bioavailable in rats. DAP exhibited no
human ERG binding, did not inhibit or serve as a substrate of CYP enzymes, and
did not appreciably bind any plasma proteins (data not shown). In addition, it
appears that DAP has a short elimination half-life, because anti-coagulation
induced by PRADAXA® returned in 20-30 minutes following an intravenous
bolus dose of DAP in rats. Moreover, DAP was stable to sterilization (survived
heating to 200° C) and to storage as a lyophilized powder at 4°C for more than one
year. Summary of anticoagulant reversal by DAP is presented in Table 2.
Table 2: Anticoagulant reversal
Trade Generic Company Blood Route of Bind Reversal
Name Name Factor Administration s Agents
Inhibited DAP
Lovenox® Enoxaparin Sanofi, ~80-90% s.c. Injection X Protamine
Sandoz/ Xa, * & DAP
Momenta,
Hibor® Bemiparin Rovi ~10-20%
IIa
Arixtra® Fondaparinux GSK Xa s.c. Injection X DAP
Eliquis® Apixaban Pfizer, Xa Oral X DAP
BMS
Xarelto® Rivaroxaban Bayer, Xa Oral X DAP
Janssen,
J&J
Argatroban® Argatroban GSK IIa s.c. Injection -- None
Pradaxa® Dabigatran Boehringer IIa Oral X DAP
etexilate Ingelheim
*Protamine partially reverses low molecular weight heparins.
Table 3: In vitro in vivo correlation
Drug Generic DLS Binding Reversal in vivo Blood Route of
Name Molar Ratio Molar Ratio Measure Factor(s) Administration
[DAP/drug] [DAP/drug] Inhibited
Rivaroxaban 9 3* Bleeding assay Xa Oral
Apixaban 10 8* Bleeding assay Xa Oral
Fondaparinux 3 130 Xa kit Xa s.c. Injection
Bemiparin 7 140 aPTT ~80-90% Xa, s.c. Injection
~10-20% IIa
Argatroban N/A N/A aPTT IIa s.c. Injection
Assumes oral bioavailabilities of 60% for rivaroxaban, 50% for apixaban, and 5%
for dabigatran; Assumes 100% bioavailability for injectable anticoagulants.
[0147] Summary of in vitro-in vivo correlation of treatment with DAP is presented
in Table 3. DLS binding molar ratio is calculated by dividing the lowest mass ratio
of DAP to anticoagulant that shows significant binding, defined as an association
in phosphate buffered saline above 50nm in apparent diameter, by the molecular
weight ratio of DAP and the anticoagulant. The molecular weights used in the
calculations were 512Da (DAP), 436Da (rivaroxaban), 460Da (apixaban), 1.7kDa
(fondaparinux), 3.6kDa (bemiparin), 628Da (dabigatran), and 509Da
(ARGATROBAN®). Reversal molar ratio was calculated similarly using the
minimal in vivo reversal dose of DAP necessary to achieve reversal as measured by
the rat tail transection bleeding assay, chromogenic anti-Xa kit, or by activated
partial thromboplastin time (aPTT). For the bleeding assay, the anticoagulant was
considered reversed if the blood loss over a period of 30 minutes after tail
transection, with the cut tail immersed in room temperature saline, was within 25%
of the control (no anticoagulant administered). As measured by the Xa kit, reversal
was achieved when the effective anticoagulant concentration was brought below
the minimum effective concentration (MEC) for anticoagulation. As measured by
aPTT, reversal was considered achieved when an anticoagulated rat aPTT returned
to within 10% of baseline. In the case of fondaparinux, although 200mg/kg DAP
was the lowest dose administered in vivo, the in vitro data indicate that
significantly lower reversal doses are possible.
[0148] The entire contents of all references, patent applications, and patents cited
throughout this application are hereby incorporated by reference herein.
EXAMPLES
[0149] The invention will be further illustrated in the following nonlimiting
Examples. These Examples are set forth to aid in the understanding of the
invention but are not intended to, and should not be construed to, limit its scope in
any way. The Examples do not include detailed descriptions of conventional
methods that are well known to those of ordinary skill in the art.
Example 1: In vitro Stability Testing of Diarginine piperazine (“DAP”)
Materials and Methods
[0150] An acetate salt of DAP was prepared as described herein. As described in
these examples, DAP solid or powder refers to the acetate salt, while DAP in
solution refers to the free base as the salt ionizes in aqueous solution. As described
in these examples, the DAP compound used was the compound of Formula VII.
[0151] The DAP powder was tested for thermal stability in two ways. DAP was
o
stored at 4 C for 7 months prior to use. Additionally, the DAP solid was tested by
o o
differential scanning calorimetry (DSC) by heating from -20 C to 200 C, back to -
o o
C and again to 200 C.
Results
[0152] DAP powder was stable at 4°C for more than 12 months. The results of
DSC are shown in Figure 1. The second heat (“2”) showed similar thermal
behavior to the first heat (“1”), indicating that DAP survived repeated heating to
o
200 C. This finding indicates that DAP is able to survive heating to temperatures
above those necessary for sterilization.
Example 2: Binding of DAP to Heparin and LMWH
Materials and Methods
[0153] Dynamic light scattering (DLS) was used to assess association of 1 mg/ml
unfractionated heparin and 1 mg/ml bemiparin (LMWH; HIBOR®), either alone or
in combination with 100 mg/ml DAP in water (mass ratios of 100:1 of DAP to
heparin or LMWH).
Results
[0154] DAP physically associated in water with both unfractionated heparin
(Figure 2) and LMWH (not shown) to form physical associations that increase the
apparent diameter. When solutions of DAP were mixed with solutions of LMWH
or unfractionated heparin, they formed particles due to their physical interactions,
which supports the theory that DAP could reverse heparin and LMWH
anticoagulation by physically associating with these molecules.
Example 3: DAP Binding to Anticoagulants as Measured by DLS.
Materials and Methods
[0155] Rivaroxaban (XARELTO®) alone, DAP alone, and DAP:rivaroxaban
combinations at mass ratios of 1:1 and 10:1 were added into an aqueous solution
and analyzed by dynamic light scattering (DLS) to assess association of the DAP
and rivaroxaban. A similar experiment was conducted on apixaban (ELIQUIS®)
alone, DAP alone, and DAP:apixaban combinations at mass ratios of 1:1, 10:1 and
100:1. Fondaparinux (ARIXTRA®) alone, DAP alone, and fondaparinux:DAP
combinations at mass ratios of 1:1, 10:1 and 100:1 were similarly tested. LMWH
(bemiparin; HIBOR®), alone, DAP alone, and LMWH:DAP combinations at mass
ratios of 1:1, 10:1, and 100:1 were also tested. The concentration of LMWH tested
was 0.1 mg/ml. Therefore, at 1:1, 0.1 mg/ml DAP was tested, at 10:1, 1 mg/ml
was tested, and at 100:1, 10 mg/ml DAP was tested.
[0156] Additionally, dabigatran alone, DAP alone, and dabigatran:DAP
combination at mass ratios of 1:1, 10:1, 100:1, 1,000:1, and 10,000:1 DAP were
tested. Finally, ARGATROBAN® alone, DAP alone, or combinations of
argatroban:DAP at mass ratios of 1:1, 10:1, 100:1, and 1,000:1 were tested.
Results
[0157] The results are shown in Figure 3 for rivaroxaban; Figure 4 for apixaban;
Figure 5 for fondaparinux (ARIXTRA®), Figure 6 for LMWH; and Figure 7 for
argatroban. Each figure shows individual peaks representing DAP and the
anticoagulant alone in aqueous solution. When the anticoagulant was mixed with
DAP at sufficiently high mass ratios, a change in size was observed. In this assay,
even a slight increase in size indicates physical interaction between the two;
however, only significant shifts in the apparent diameter are used in assessing the
in vitro in vivo correlation. Apparent diameter is a measure of the degree of
interaction.
Example 4: DAP Reversal of LMWH Anticoagulation In Vivo
Materials and Methods
[0158] A male albino rat, weighing 470 g, was administered 10 mg of bemiparin
(an overdose of LMWH) by subcutaneous injection. aPTT time was measured
over the course of five hours. Four hours after LMWH administration, the rat
received an intravenous dose of 200 mg/kg of DAP (100mg DAP).
Results
[0159] Upon administration of LMWH, the aPTT rose from 53 to 246 seconds
over the course of four hours. Intravenous administration of 200 mg/kg of DAP
(100 mg DAP) brought aPTT time below baseline within 60 minutes (Figure 8).
Example 5: DAP Reversal of Dabigatran (PRADAXA®) Anticoagulation
In Vivo; an Overdose Study
Materials and Methods
[0160] A male albino rat, weighing 430 g, was administered 40 mg/kg of
PRADAXA® (20mg PRADAXA®; overdose of PRADAXA®) by oral gavage.
[0161] Approximately 2 hours into PRADAXA® treatment, 200 mg/kg DAP
(100 mg DAP) was administered as an intravenous bolus injection. Approximately
2 hours later, the rat was administered a dose of 100 mg/kg of DAP (50mg DAP).
In another hour, the rat was administered another dose of 100 mg/kg of DAP
(50 mg DAP). aPTT was measured throughout the course of the entire treatment.
Results
[0162] The results are shown in Figures 9 and 13. 2 hours following
administration of PRADAXA®, aPTT rose from 43 to 81 seconds, showing
significant anti-coagulation. 100 mg of DAP was administered as an intravenous
bolus injection, which brought aPTT down below baseline within 25 minutes.
2 hours later, aPTT had risen back to 79 seconds and the rat was administered a
dose of 50 mg of DAP. Within 30 minutes, aPTT was brought down below
baseline. Both times, within 60 minutes following DAP administration, the aPTT
levels had returned above baseline. After the second dose of DAP, the aPTT rose
to 53 seconds. A third dose of DAP, 100 mg/kg of DAP (50 mg DAP), was
administered intravenously and the aPTT was dropped to baseline within 20
minutes. Figure 13 demonstrates a similar experiment where, after 15.5 mg/kg
administration of PRADAXA®, the aPTT returned to normal within about 30
minutes of initiation of 100 mg/kg DAP treatment.
Example 6: DAP Reversal of Unfractionated Heparin (“UHF”)
Anticoagulation In Vivo.
Materials and Methods
[0163] A male albino rat, weighing 515 g, was administered 10 mg /kg of
unfractionated heparin (5 mg UFH) by subcutaneous injection.
[0164] 200 mg/kg of DAP (100 mg DAP) was administered as two intravenous
bolus injections after UFH administration. Subsequently, the rat was administered
a dose of 400mg/kg of DAP (200mg of DAP). aPTT was measured throughout the
course of the entire treatment.
Results
[0165] As demonstrated in Figure 10, the aPTT time rose significantly from 28 to
102 seconds over the course of one hour after administration of heparin. 100 mg
of DAP was administered intravenously and it brought aPTT time to 48 seconds in
minutes. Within 1 hour, aPTT rose to 120 seconds, then another 100mg of DAP
was administered intravenously. In 15 minutes, the aPTT was lowered to 47
seconds. Within 1 hour, aPTT rose to 96 seconds, then a dose of 200mg of DAP
was administered intravenously. 10 minutes after, aPTT dropped to 33 seconds.
Example 7: DAP Reversal of Rivaroxaban (XARELTO®) Anticoagulation
In Vivo
Materials and Methods
[0166] 5 mg /kg rivaroxaban (XARELTO®) was orally administered to rats.
After four hours, 5 mg/kg of DAP (2 mg DAP) was administered intravenously.
aPTT were measured at zero, 15, 30, 45, 60 and 240 minutes, prior to
administration of DAP. aPTT was again measured at about 5, 10, 25, 35, 45, 60,
120, and 240 minutes after DAP administration.
Results
[0167] The results are shown in Figure 11. DAP effectively reversed the
rivaroxaban (XARELTO®) anticoagulation in vivo in rats.
Example 8: DAP Reversal of Fondaparinux (ARIXTRA®)
Anticoagulation In Vivo.
Materials and Methods
[0168] 5 mg/kg fondaparinux was administered subcutaneously to rats.
200 mg/kg DAP was administered intravenously after 2 hours. Activity was
measured by chromogenic 510k cleared Factor Xa Assay (Biophen) at 10, 20, 30
and 60 minutes after DAP adminsitration.
Results
[0169] Figure 12 demonstrates DAP-mediated reversal of fondaparinux
anticoagulation within 10 minutes of administration.
Example 9: Intravenous DAP does not influence aPTT
Materials and Methods
[0170] 0, 2, 10, 25, 50 or 100 mg DAP were administered intravenously to male,
weight matched CD rats and aPTT was measured.
Results
[0171] The results shown in Figure 16 demonstrate that DAP administered
intravenously did not influence aPTT in a dose dependent fashion in the absence of
anticoagulants. Error bars represent standard error from seven aPTT
measurements averaged over 90 minutes.
Example 10: DAP Reversal of Anticoagulation in a Rat Tail Transection
Model.
Materials and Methods
[0172] Three rats each were administered 2 mg of rivaroxaban. One rat received a
sham reversal containing no DAP, the second received 2.5 mg of DAP, and the
third received 12.5 mg DAP. A fourth fat received sham anticoagulant and
reversal doses (“sham”). 20 minutes after the reversal dose, tails were transected
1 mm from the tip, placed in room temperature saline, and blood loss was collected
for 30 minutes and then weighed.
[0173] Same procedures were used with 1.25 mg apixaban (ELIQUIS®) alone or
in combination with 5 or 12.5 mg DAP; with 15.5 mg dabigatran etexilate
(PRADAXA®) alone or in combination with 5 or 12.5 mg DAP; and with 5 mg
edoxaban (LIXIANA®) alone or in combination with 12.5 mg DAP.
Results
[0174] The results are shown in Figure 15 for rivaroxaban, in Figure 16 for
apixaban, in Figure 17 for edoxaban, and in Figure 18 for dabigatran etexilate.
The rat tail transection bleeding assay is analogous to the clinical situation in
which acute anticoagulant reversal is needed. Results show that DAP effectively
reversed anticoagulant activity leading to statistically significant reduction in blood
loss compared to rats receiving anticoagulant only.
Example 11: DAP Reversal of Rivaroxaban (XARELTO®) Anticoagulation
in Freshly Drawn Human Blood Ex Vivo.
Materials and Methods
[0175] Human blood was drawn from a volunteer. Rivaroxaban at 0.25 µg/ml was
added alone or in combination with 50 µg/ml DAP. Controls contained 50 µg/ml
DAP or saline. aPTT was measured within 2 minutes of blood collection.
Results
[0176] Figure 19 demonstrates that administration of DAP led to a reversal of
rivaroxaban-induced anticoagulation in freshly drawn human blood, as measured
by aPTT. Error bars represent standard error from three independent experiments.
Example 12: DAP Reversal of Rivaroxaban and Apixaban Anticoagulation
in Human Plasma Ex Vivo
Materials and Methods
[0177] 218 µg/L or 459 µg/L of rivaroxaban was added to human plasma, with or
without 1,250 µg/L or 6,250 µg/L of DAP, respectively. Similarly, 156 µg/L or
313 µg/L of apixaban was added to human plasma with or without 1,156 µg/L or
3,125 µg/L of DAP, respectively. DAP effect on anticoagulation was measured by
510k cleared Biophen anti-Factor Xa chromogenic assay. Rivaroxaban
concentrations were determined by comparison with plasma calibration standards,
while apixaban concentrations were inferred from stock solution dilutions as
calibration standards are not yet available.
Results
[0178] For both concentrations of rivaroxaban and apixaban, DAP returned the
effective anticoagulant concentration to below the minimum effective
concentration. Figure 20 shows the results for rivaroxaban and Figure 21 shows
the results for apixaban.
Example 13: DAP Dose-Dependent Reversal of Rivaroxaban
Anticoagulation in Human Plasma Ex Vivo
Materials and Methods
[0179] 218 µg/L rivaroxaban was added to human plasma either alone or in
combination with 1.25, 12.5, 125, or 1,250 µg/L of DAP. Factor Xa activity was
measured by 510k cleared Biophen anti-Xa chromogenic assay kit. Rivaroxaban
concentrations were determined by comparison with plasma calibration standards.
Results
[0180] Figure 22 demonstrates that DAP was effective in dose-dependent reversal
of rivaroxaban anticoagulation in human plasma, as demonstrated by its effect on
rivaroxaban concentration (measured by Factor Xa activity assay).
[0181] The term ‘comprising’ as used in this specification and claims means
‘consisting at least in part of’. When interpreting statements in this specification
and claims which includes the ‘comprising’, other features besides the features
prefaced by this term in each statement can also be present. Related terms such as
‘comprise’ and ‘comprised’ are to be interpreted in similar manner.
IN THIS SPECIFICATION WHERE REFERENCE HAS BEEN MADE TO
PATENT SPECIFICATIONS, OTHER EXTERNAL DOCUMENTS, OR OTHER
SOURCES OF INFORMATION, THIS IS GENERALLY FOR THE PURPOSE
OF PROVIDING A CONTEXT FOR DISCUSSING THE FEATURES OF THE
INVENTION. UNLESS SPECIFICALLY STATED OTHERWISE,
REFERENCE TO SUCH EXTERNAL DOCUMENTS IS NOT TO BE
CONSTRUED AS AN ADMISSION THAT SUCH DOCUMENTS, OR SUCH
SOURCES OF INFORMATION, IN ANY JURISDICTION, ARE PRIOR ART,
OR FORM PART OF THE COMMON GENERAL KNOWLEDGE IN THE ART.
Claims (41)
1. A compound represented by formula II: (II) , or a pharmaceutically acceptable salt thereof, wherein: L and L’ are the same or different and are substituted or unsubstituted alkylene chains that is C1 to C10; M and M’ are the same or different and are substituted or unsubstituted alkylene chain that is C1 to C10 that attaches to Y and to Y’, respectively; and Y and Y’ are each ; wherein the substituents of the C 1 to C alkylene chains are selected from the group consisting of alkyl, hydroxyl, 10 hydroxyl alkyl, amino, amino alkyl and alkyl alkoxy.
2. The compound of claim 1, wherein L and/or L’ is a substituted or unsubstituted alkylene chain that is C to C . 1 6
3. The compound of claim 1, wherein the compound is represented by formula III: (III) , or a pharmaceutically acceptable salt thereof.
4. The compound of claim 3, wherein the compound is represented by formula IV: (IV) , or a pharmaceutically acceptable salt thereof, wherein n is 3 to 5, m is 3 to 6 and G is selected from –NH and OH. 2
5. The compound of claim 4, wherein G is amino.
6. A compound of claim 5, wherein the compound is represented by formula V: (V) , or a pharmaceutically acceptable salt thereof.
7. A compound of claim 5, wherein the compound is represented by formula VI: (VI) , or a pharmaceutically acceptable salt thereof.
8. A compound of claim 5, wherein the compound is represented by formula VII: (VII) , or a pharmaceutically acceptable salt thereof.
9. A compound of claim 5, wherein the compound is represented by formula VIII: (VIII) , or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising the compound of any one of claims 1-9 and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10, wherein the composition is adapted for enteral administration.
12. The pharmaceutical composition of claim 11, wherein the composition is adapted for oral administration.
13. The pharmaceutical composition of claim 12, wherein the composition is a daily dosage that comprises the compound in an amount of about 0.01 mg/kg to about 100 mg/kg of body weight of a patient.
14. The pharmaceutical composition of claim 13, wherein the daily dosage composition comprises the compound in an amount of about 0.01 mg/kg to about 25 mg/kg of body weight of the patient.
15. The pharmaceutical composition of claim 12, wherein the composition is in the form of a capsule or tablet.
16. The pharmaceutical composition of claim 12, wherein the composition is an aqueous solution.
17. The pharmaceutical composition of claim 10, wherein the composition is adapted for parenteral administration.
18. The pharmaceutical composition of claim 17, wherein the composition is adapted for intravenous or subcutaneous administration.
19. A use of a compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for completely or partially reversing an anticoagulant effect of a coagulation inhibitor in a subject in need thereof.
20. The use of claim 19, wherein the coagulation inhibitor is selected from the group consisting of an unfractionated heparin, low molecular weight heparin (LMWH), Factor IIa inhibitor, and Factor Xa inhibitor.
21. The use of claim 20, wherein the coagulation inhibitor is a factor Xa inhibitor.
22. The use of claim 21, wherein the factor Xa inhibitor is selected from the group consisting of rivaroxaban, apixaban, edoxaban, and fondaparinux.
23. The use of claim 19, wherein the subject is a mammal.
24. The use of claim 23, wherein the subject is a human.
25. The use of claim 19, wherein the complete or partial reversal of an anticoagulant effect of a coagulation inhibitor is measured by anti-factor Xa activity assay.
26. The use of claim 19, wherein the subject in need thereof is a subject in whom acute or planned reversal of anticoagulation is indicated.
27. The use of claim 26, wherein the subject in whom acute or planned reversal of anticoagulation is indicated is a subject suffering from anticoagulant overdose, a subject suffering from hemorrhage, a subject requiring planned surgical intervention, a subject undergoing an invasive or non-invasive procedure requiring a biopsy, a subject undergoing a procedure wherein a procedural error may result in hemorrhage if the subject remains anticoagulated, or a subject requiring spinal or epidural anesthesia.
28. The use of claim 26, wherein the subject in need thereof is a subject receiving anticoagulation for stroke prevention, cardiac surgical and diagnostic procedures, cardiac arrhythmias, deep vein thrombosis (DVT) prevention, pulmonary embolism, or generally for the prevention of pathologic blood clots.
29. The use of claim 20, wherein the coagulation inhibitor is a LMWH, and wherein the LMWH is selected from the group consisting of bemiparin, certoparin, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, and tinzaparin.
30. The use of claim 19, wherein the compound or the pharmaceutically acceptable salt thereof is to be administered at a dose mass ratio of between about 0.01:1 to about 1000:1 of the compound or the pharmaceutically acceptable salt thereof to anticoagulant.
31. The use of claim 30, wherein the compound or the pharmaceutically acceptable salt thereof is to be administered at a dose mass ratio of about 10:1 of the compound or the pharmaceutically acceptable salt thereof to anticoagulant.
32. The use of claim 19, wherein the medicament is to be administered with at least one additional therapeutic agent.
33. The use of claim 32, wherein the at least one additional therapeutic agent is vitamin K.
34. The use of claim 19, wherein the compound is to be orally administered.
35. The use of claim 19, wherein about 0.01 mg/kg to about 100 mg/kg of body weight per day of the compound is to be orally administered.
36. A diagnostic kit comprising the compound of any one of claims 1-9.
37. The kit of claim 36, wherein the kit is to be used for determining an anticoagulant concentration in blood.
38. The compound as described in any one of claims 1-9, substantially as herein described and with reference to any example thereof.
39. The pharmaceutical composition as described in any one of claims 10-18, substantially as herein described and with reference to any example thereof.
40. The use as described in any one of claims 19-35, substantially as herein described and with reference to any example thereof.
41. The kit of claim 36 or claim 37, substantially as herein described and with reference to any example thereof.
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161564559P | 2011-11-29 | 2011-11-29 | |
US61/564,559 | 2011-11-29 | ||
US201261614292P | 2012-03-22 | 2012-03-22 | |
US61/614,292 | 2012-03-22 | ||
US201261641698P | 2012-05-02 | 2012-05-02 | |
US61/641,698 | 2012-05-02 | ||
US201261666291P | 2012-06-29 | 2012-06-29 | |
US61/666,291 | 2012-06-29 | ||
PCT/US2012/066938 WO2013082210A1 (en) | 2011-11-29 | 2012-11-29 | Anticoagulant reversal agents |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ625337A NZ625337A (en) | 2016-11-25 |
NZ625337B2 true NZ625337B2 (en) | 2017-02-28 |
Family
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